DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

such as dimethyl sulfoxide. Amiodarone’s effects may
be mediated by perturbation of the lipid environment of
the ion channels (Herbette et al., 1988). Amiodarone
blocks inactivated Na + channels and has a relatively
rapid rate of recovery (time constant ~1.6 s) from block.
It also decreases Ca 2+ current and transient outward
delayed-rectifier and inward rectifier K + currents and
exerts a noncompetitive adrenergic blocking effect.
Amiodarone potently inhibits abnormal automaticity
and, in most tissues, prolongs APD. Amiodarone
decreases conduction velocity by Na + channel block and
by a poorly understood effect on cell–cell coupling that
may be especially important in diseased tissue (Levine
et al., 1988). Prolongations of the PR, QRS, and QT
intervals and sinus bradycardia are frequent during
chronic therapy. Amiodarone prolongs refractoriness in
all cardiac tissues; Na + channel block, delayed repolarization
owing to K + channel block, and inhibition of
cell–cell coupling all may contribute to this effect.
Adverse Effects. Hypotension owing to vasodilation and depressed
myocardial performance are frequent with the intravenous form of
amiodarone and may be due in part to the solvent. Although
depressed contractility can occur during long-term oral therapy, it is
unusual. Despite administration of high doses that would cause
serious toxicity if continued long term, adverse effects are unusual
during oral drug-loading regimens, which typically require several
weeks. Occasionally during the loading phase, patients develop nausea,
which responds to a decrease in daily dose.
Adverse effects during long-term therapy reflect both the size
of daily maintenance doses and the cumulative dose, suggesting that
tissue accumulation may be responsible. The most serious adverse
effect during chronic amiodarone therapy is pulmonary fibrosis,
which can be rapidly progressive and fatal. Underlying lung disease,
doses of 400 mg/day or more, and recent pulmonary insults such as
pneumonia appear to be risk factors (Dusman et al., 1990). Serial
chest X-rays or pulmonary function studies may detect early amiodarone
toxicity, but monitoring plasma concentrations has not been
useful. With low doses, such as 200 mg/day or less used in atrial fibrillation,
pulmonary toxicity is unusual. Other adverse effects during
long-term therapy include corneal microdeposits (which often are
asymptomatic), hepatic dysfunction, neuromuscular symptoms
(most commonly peripheral neuropathy or proximal muscle weakness),
photosensitivity, and hypo- or hyperthyroidism. The multiple
effects of amiodarone on thyroid function are discussed further in
Chapter 39. Treatment consists of withdrawal of the drug and supportive
measures, including corticosteroids, for life-threatening pulmonary
toxicity; reduction of dosage may be sufficient if the drug is
deemed necessary and the adverse effect is not life-threatening.
Despite the marked QT prolongation and bradycardia typical of
chronic amiodarone therapy, torsades de pointes and other druginduced
tachyarrhythmias are unusual.
Clinical Pharmacokinetics. Amiodarone’s oral bioavailability is
~30%, presumably because of poor absorption. This incomplete
bioavailability is important in calculating equivalent dosing regimens
when converting from intravenous to oral therapy. The drug
is distributed in lipid; e.g., heart-tissue-to-plasma concentration
ratios of greater than 20:1 and lipid-to-plasma ratios of greater than
300:1 have been reported. After the initiation of amiodarone therapy,
increases in refractoriness, a marker of pharmacologic effect,
require several weeks to develop. Amiodarone undergoes hepatic
metabolism by CYP3A4 to desethyl-amiodarone, a metabolite with
pharmacologic effects similar to those of the parent drug. When
amiodarone therapy is withdrawn from a patient who has been
receiving therapy for several years, plasma concentrations decline
with a t 1/2
of weeks to months. The mechanism whereby amiodarone
and desethyl-amiodarone are eliminated is not well established.
A therapeutic plasma amiodarone concentration range of
0.5-2 g/mL has been proposed. However, efficacy apparently
depends as much on duration of therapy as on plasma concentration,
and elevated plasma concentrations do not predict toxicity
(Dusman et al., 1990). Because of amiodarone’s slow accumulation
in tissue, a high-dose oral loading regimen (e.g., 800-1600 mg/day)
usually is administered for several weeks before maintenance therapy
is started. Maintenance dose is adjusted based on adverse
effects and the arrhythmias being treated. If the presenting arrhythmia
is life-threatening, dosages of 300 mg/day normally are used
unless unequivocal toxicity occurs. On the other hand, maintenance
doses of 200 mg/day are used if recurrence of an arrhythmia
would be tolerated, as in patients with atrial fibrillation. Because of
its very slow elimination, amiodarone is administered once daily,
and omission of one or two doses during chronic therapy rarely
results in recurrence of arrhythmia.
Dosage adjustments are not required in hepatic, renal, or cardiac
dysfunction. Amiodarone potently inhibits the hepatic metabolism
or renal elimination of many compounds. Mechanisms identified
to date include inhibition of CYP3A4, CYP2C9 and P-glycoprotein
(Chapters 5 and 6). Dosages of warfarin, other anti-arrhythmics (e.g.,
flecainide, procainamide, quinidine), or digoxin usually require
reduction during amiodarone therapy.
Bretylium. Bretylium is a quaternary ammonium compound that prolongs
cardiac action potentials and interferes with reuptake of norepinephrine
by sympathetic neurons. In the past, bretylium was used
to treat VF and prevent its recurrence; the drug is currently not available
in the U.S.
Digoxin
CH 3 H
H
H OH
O
CH H
3
O
OH
H
O
3
DIGOXIN
OH CH3
Digitoxin has H at C12 in place of the OH.
O
H
O
837
CHAPTER 29
ANTI-ARRHYTHMIC DRUGS